A physiologically active substance, called "pulmonary surfactant" exists in the animal lungs. Pulmonary surfactant is mainly biosynthesized in and secreted from type II epithelial cells of the alveoli and is known to be present as an internal lining of the wall of the whole respiratory tract including the alveolar region. It is known that pulmonary surfactant reduces the surface tension of the alveoli and prevents collapse of the alveoli. In addition, pulmonary surfactant plays an important role as a defense mechanism in the entire respiratory tract. It is well documented that it prevents pulmonary edema and has preventative effects on bacterial or viral infection or on atmospheric pollutants and antigens which induce inflammation of the respiratory tract or asthmatic attacks. Pulmonary surfactant is also known to play an important role in lubricating the respiratory lumen and expelling foreign matter from the respiratory tract by activating mucociliary transport.
Pulmonary surfactant is a complex mixture of proteins and phospholipids. There are four known proteins in alveolar surfactant; SP-A, -B, -C, and -D. SP-B and -C are small, very hydrophobic proteins that interact with phospholipids to lower alveolar surface tension. SP-D is a 43 kDa apoprotein of uncertain function. Like SP-A, SP-D has collagen-like domains. SP-A is a moderately hydrophobic 29-36 kDa apoprotein. It reportedly stabilizes the phospholipid structure and promotes interactions between phospholipids. It also appears to be important in regulating surfactant secretion. These proteins, together with phospholipids, are secreted from alveolar type II pneumocytes and form the air-liquid interphase in the alveoli and comprise what is referred to herein as "alveolar surfactant".
Because of its various physiological functions in the respiratory system, qualitative and quantitative changes of pulmonary surfactant seem to be related to the onset of or aggravation of many conditions. Accordingly, the modulation of secretion of pulmonary surfactant may make it possible to treat or prevent various respiratory conditions, for example acute respiratory failure such as infant or adult respiratory distress syndrome, bronchitis, infectious disease and chronic respiratory failure.
Infantile respiratory distress syndrome which may lead to acute respiratory failure is caused by a deficiency of pulmonary surfactant. A quantitative surfactant deficiency is quite common in preterm infants, causing neonatal respiratory distress syndrome (NRDS). About 10,000-12,000 cases of NRDS occur each year, with mortality of about 15%. Surfactant inactivation, and therefore a relative deficiency in the amount of surfactant secreted by the lung, is thought to be involved in the development of adult respiratory distress syndrome (ARDS). ARDS affects about 50,000-60,000 people in the U.S. yearly and carries a mortality of 50%. Unlike neonatal RDS, for which surfactant replacement therapy is costly but feasible, ARDS is extremely costly to treat in this fashion (requiring up to one hundred times as much surfactant as does NRDS). Thus, new methods of treating ARDS are desired. It has also been reported that in chronic disease associated with respiratory failure, abnormality of pulmonary surfactant may occur.
There is substantial evidence that surfactant secretion is controlled in part by a feedback inhibition circuit involving SP-A and a receptor for SP-A. SP-A inhibits surfactant phospholipid secretion in cultured type II alveolar cells. This inhibition appears to be mediated by a high affinity cell membrane receptor specific for SP-A. Chemical modification of SP-A that alters its interaction with its receptor prevents these effects. Thus, a type II alveolar cell membrane protein that binds surfactant protein A is a major physiologic regulator of pulmonary function. Understanding of this receptor's function and structure permits manipulation of surfactant secretion both in physiological states and in pathologic states when insufficient surfactant is produced (neonatal respiratory distress syndrome: RDS), when surfactant is present in normal amounts but is abnormally inhibited by other proteins (adult RDS), or when surfactant is produced in abnormally large quantities (alveolar proteinosis). Until now, the nature of this binding protein has been unclear.
Monoclonal antibodies have been proposed as a possible means of detecting and treating tumors (Weinstein et al., Cancer Metastasis: Experimental and Clinical Strategies, Alan R. Liss, Inc., 1986, pp. 169-80). Monoclonal antibodies specific for identified antigens on the membranes of tumor cells have been used in attempts to direct imaging agents and therapeutics, which often have very detrimental side effects, to the cancerous cells. An advantage of monoclonal antibodies over classical diagnostic agents and treatments is that with monoclonal antibodies it should be possible to specifically target selected cells. Clinical studies with monoclonal antibodies, however, have frequently been unsatisfactory. One of the reasons for this is the difficulty in identifying an antigen found only on a specific target or tissue. Monoclonal antibodies, like all other drugs and therapeutic agents, have little value unless they can be targeted to a specific target or tissue.
The development of two monoclonal antibodies directed against the antigen binding regions of antibodies to surfactant proteins have recently been reported (D. S. Strayer, Am. J. Pathol. 1991, 138, 1085-1095 and D. S. Strayer, Biol. Neonat. 1992, 61, 1-14). These independently derived anti-idiotype antibodies, A2C and A2R, bind anti-SP-A antibodies and prevent them from binding surfactant protein. These antibodies have been described in terms of their functional characteristics but have not heretofore been structurally characterized. These antibodies may be useful in identifying cell membrane molecules on type II cells that are important in regulating alveolar surfactant secretion. In addition, it has now been found that these antibodies may be used as targeting agents for assisting in the delivery of therapeutic agents to type II cells or bronchial epithelial cells.